WO2016208709A1 - 1-(アシルオキシ)アルキルカルバメート誘導体の新規な製造方法 - Google Patents
1-(アシルオキシ)アルキルカルバメート誘導体の新規な製造方法 Download PDFInfo
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- WO2016208709A1 WO2016208709A1 PCT/JP2016/068796 JP2016068796W WO2016208709A1 WO 2016208709 A1 WO2016208709 A1 WO 2016208709A1 JP 2016068796 W JP2016068796 W JP 2016068796W WO 2016208709 A1 WO2016208709 A1 WO 2016208709A1
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- 0 CC(*)C(O[C@](C)OC(NCCC[C@@](Cc1c[n](C(CC2)CCC2=C)cn1)C(O)=O)=O)=O Chemical compound CC(*)C(O[C@](C)OC(NCCC[C@@](Cc1c[n](C(CC2)CCC2=C)cn1)C(O)=O)=O)=O 0.000 description 1
- SOSZIDHLTYALRP-OLOOMHLZSA-N CC(C)C(OC(C)OC(NCCC[C@@H](Cc1c[n]([C@H]2CC[C@H](C)CC2)cn1)C(O)=O)=O)=O Chemical compound CC(C)C(OC(C)OC(NCCC[C@@H](Cc1c[n]([C@H]2CC[C@H](C)CC2)cn1)C(O)=O)=O)=O SOSZIDHLTYALRP-OLOOMHLZSA-N 0.000 description 1
- SNSKJWOMYHITPC-UHFFFAOYSA-N CC(C)C(OC(C)OC(OC(C(F)(F)F)C(F)(F)F)=O)=O Chemical compound CC(C)C(OC(C)OC(OC(C(F)(F)F)C(F)(F)F)=O)=O SNSKJWOMYHITPC-UHFFFAOYSA-N 0.000 description 1
- SNSKJWOMYHITPC-RXMQYKEDSA-N CC(C)C(O[C@@H](C)OC(OC(C(F)(F)F)C(F)(F)F)=O)=O Chemical compound CC(C)C(O[C@@H](C)OC(OC(C(F)(F)F)C(F)(F)F)=O)=O SNSKJWOMYHITPC-RXMQYKEDSA-N 0.000 description 1
- AEHFUSPLVGWEEP-YDHLFZDLSA-N C[C@H](CC1)CC[C@@H]1[n]1cnc(C[C@H](CCCN)C(O)=O)c1 Chemical compound C[C@H](CC1)CC[C@@H]1[n]1cnc(C[C@H](CCCN)C(O)=O)c1 AEHFUSPLVGWEEP-YDHLFZDLSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/96—Esters of carbonic or haloformic acids
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/01—Carboxylic ester hydrolases (3.1.1)
- C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
Definitions
- the present invention relates to a novel method for producing a 1- (acyloxy) alkyl carbamate derivative and a fluorous alkyl carbonate derivative used in the method.
- Prodrugs refer to pharmaceuticals that are converted into active ingredients by reactions with enzymes, gastric acid, and the like in vivo. Prodrugation is performed for the purposes of (1) improving absorption into the body, (2) reducing side effects, (3) acting on specific organs, and (4) sustaining action. ing.
- the 1- (acyloxy) alkoxycarbonyl group is used as a prodrug for various pharmaceutical molecules having an amino group or the like.
- a pharmaceutical molecule having an amino group is converted into a 1- (acyloxy) alkyl carbamate derivative by introducing the group into a prodrug (Non-patent Documents 1 and 2).
- Patent Document 1 discloses 1- (acyloxy) alkylcarbamate derivatives (Examples 20, 22, 23, and Patent Document 1) as prodrugs of compounds exhibiting TAFIa inhibitory activity (Examples 15 and 40 of Patent Document 1). 27, 28, 29, 30, 31, and 32) are shown.
- methods for synthesizing 1- (acyloxy) alkylcarbamate derivatives methods shown in Patent Documents 2 to 8 are known. However, these methods have drawbacks such as requiring multi-step reaction steps, low yields, and producing by-products that are difficult to remove.
- An object of the present invention is to provide an efficient and simple method for producing a 1- (acyloxy) alkylcarbamate derivative.
- the present inventors have found that a 1- (acyloxy) alkyl carbamate derivative can be produced using a fluorous alkyl carbonate derivative. It was found that the fluoroalcohol produced as a by-product can be easily removed by a simple concentration operation, and a 1- (acyloxy) alkyl carbamate derivative having a good quality can be produced efficiently and simply. That is, the present invention includes the following inventions.
- R 1 represents a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group
- R 2 represents a C 1 -C 4 alkyl group or a hydrogen atom
- A represents a fluoroalkyl group.
- the fluorous alkyl group represents a C 2 to C 11 alkyl group in which 40% or more of hydrogen atoms are substituted with fluorine atoms
- R 1 represents a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group
- R 2 represents a C 1 -C 4 alkyl group or a hydrogen atom
- A represents a fluoroalkyl group.
- the fluoroalkyl group is a C 2 to C 11 alkyl group in which 40% or more of hydrogen atoms are substituted with fluorine atoms.
- (7) The compound according to (6), wherein the fluoroalkyl group is a 1,1,1,3,3,3-hexafluoro-2-propyl group.
- R 1 is an isopropyl group and R 2 is a methyl group.
- R 1 represents a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group
- R 2 represents a C 1 -C 4 alkyl group or a hydrogen atom
- A represents a fluoroalkyl group.
- the fluorous alkyl group represents a C 2 to C 11 alkyl group in which 40% or more of hydrogen atoms have been replaced by fluorine atoms
- the manufacturing method of the compound represented by these (15) The production method according to (14), wherein the enzyme is a lipase derived from Candida antarctica, a lipase derived from Candida rugosa, or a lipase derived from Thermomyces lanuginosus. (16) The production method according to (15), wherein the enzyme is a lipase derived from Candida antarctica. (17) The production method according to (16), wherein the enzyme is CHIRAZYME L-2, C4. (18) The production method according to any one of (14) to (17), wherein the inert solvent is a solvent containing a buffer solution.
- the “C 1 -C 4 alkyl group” in R 1 and R 2 means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl Group, n-butyl group, sec-butyl group and tert-butyl group.
- the “C 1 -C 4 alkyl group” in R 1 is preferably a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, and more preferably an isopropyl group or a tert-butyl group. Most preferably, it is an isopropyl group.
- the “C 3 -C 6 cycloalkyl group” in R 1 means a group consisting of a saturated hydrocarbon ring having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Can do.
- the “C 3 -C 6 cycloalkyl group” in R 1 is preferably a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, more preferably a cyclopentyl group or a cyclohexyl group, most preferably It is a cyclohexyl group.
- R 1 as a whole is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, or a cyclohexyl group, more preferably an isopropyl group, a tert-butyl group, or a cyclohexyl group, Preferably, it is an isopropyl group.
- the “C 1 -C 4 alkyl group” in R 2 is preferably a methyl group, an ethyl group, or an isopropyl group, more preferably a methyl group or an ethyl group, and most preferably methyl. It is a group.
- R 2 as a whole is preferably a hydrogen atom, a methyl group, an ethyl group, or an isopropyl group, more preferably a hydrogen atom, a methyl group, or an ethyl group, and most preferably a methyl group. is there.
- fluoroalkyl group in A means a C 2 to C 11 alkyl group in which 40% or more of hydrogen atoms are substituted with fluorine atoms, and examples thereof include 2,2-difluoroethyl group, 2,2,2- Trifluoroethyl group, 2,2,3,3,3-pentafluoro-1-propyl group, 1,1,1,3,3,3-hexafluoro-2-propyl group, 2,2,3,4 , 4,4-hexafluoro-1-butyl group, 2,2,3,3,4,4,4-heptafluoro-1-butyl group, nonafluoro-tert-butyl group, 2,2,3,3 4,4,5,5-octafluoro-1-pentyl group, 1H, 1H-nonafluoro-1-pentyl group, 1H, 1H, 2H, 2H-nonafluoro-1-hexyl group, 1H, 1H, 7H-dodecaflu
- the “fluoroalkyl group” in A is preferably a 2,2,2-trifluoroethyl group, a 2,2,3,3,3-pentafluoro-1-propyl group, a 1,1,1,3, 3,3-hexafluoro-2-propyl group, 2,2,3,4,4,4-hexafluoro-1-butyl group, 2,2,3,3,4,4,4-heptafluoro-1 -Butyl group or nonafluoro-tert-butyl group, more preferably 2,2,2-trifluoroethyl group, 2,2,3,3,3-pentafluoro-1-propyl group, 1, 1,1,3,3,3-hexafluoro-2-propyl group, 2,2,3,4,4,4-hexafluoro-1-butyl group, or 2,2,3,3,4,4 , 4-heptafluoro-1-butyl group, most preferably 1,1,1,3,3,3-hexyl Fluoro-2-propyl group.
- the production method of the present invention can be carried out according to the following.
- Step 1 This step is carried out according to the formula (IV) [wherein R 1 represents a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group, and R 2 represents a C 1 -C 4 alkyl group or a hydrogen atom. ] And a compound represented by formula (V) [wherein A represents a fluoroalkyl group. (Here, the fluorous alkyl group is a C 2 to C 11 alkyl group in which 40% or more of hydrogen atoms are substituted with fluorine atoms.)]]] Is brought into contact with the compound represented by formula (I) [here And R 1 , R 2 and A are as defined above. ] (Ie, a fluorous alkyl carbonate derivative).
- the compound represented by the formula (IV) is Bioorg. Med. Chem. Lett. , 7, p. 1811-1816 (1997); Med. Chem. , 31, p. 318-322 (1988) or a method analogous thereto.
- the compound represented by the formula (V) is fluorous alcohol, and a commercially available product can be used.
- the solvent used in this step is not particularly limited as long as it does not inhibit the reaction, but acetonitrile, dichloromethane, chloroform, methanol, ethanol, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane , Ethyl acetate, hexane, pentane, benzene, toluene, chlorobenzene, acetone, 2-butanone, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, water, or these A mixed solvent can be mentioned, and acetonitrile is preferred.
- the amount of the compound represented by formula (V) used in this step is usually 1 to 10 equivalents, preferably 1.5 to 4 equivalents, relative to the compound represented by formula (IV). It is.
- This step preferably uses a base.
- the base include triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] undec-7-ene Preferred is triethylamine.
- the amount of the base is usually 1 to 10 equivalents, preferably 1 to 1.2 equivalents, relative to the compound represented by formula (IV).
- the reaction temperature in this step is usually ⁇ 40 ° C. to 80 ° C., and preferably ⁇ 10 ° C. to 15 ° C.
- the reaction time in this step is usually 1 hour to 72 hours, preferably 2 hours to 6 hours.
- Step 2 is a compound represented by the formula (I) [wherein R 1 represents a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group, R 2 represents a C 1 -C 4 alkyl group or a hydrogen atom, A represents a fluoroalkyl group. (Here, the fluorous alkyl group is a C 2 to C 11 alkyl group in which 40% or more of hydrogen atoms are substituted with fluorine atoms.)] And a compound represented by the formula (II The compound represented by formula (III) [wherein R 1 and R 2 are as defined above].
- the compound represented by the formula (II) or a salt thereof can be produced by the method described in WO 2011/115064 or a method analogous thereto (the compound represented by the formula (II) is described as Example 15.
- the p-toluenesulfonate / anhydride of the compound is described as Example 40).
- the solvent used in this step is not particularly limited as long as it does not inhibit the reaction, but acetonitrile, dichloromethane, chloroform, methanol, ethanol, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane , Ethyl acetate, hexane, pentane, benzene, toluene, chlorobenzene, acetone, 2-butanone, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, water, or these A mixed solvent can be mentioned, and acetonitrile is preferred.
- the amount of the compound represented by formula (I) used in this step is usually 1 to 15 equivalents, preferably 1 to 1.5 equivalents, relative to the compound represented by formula (II). It is.
- This step preferably uses a base.
- the base include triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-7-ene Preferred is triethylamine.
- the amount of the base is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the compound represented by the formula (II).
- the compound represented by the formula (II) is an acid addition salt with an acid (for example, hydrohalides such as hydrofluorate, hydrochloride, hydrobromide, hydroiodide; nitrate, peroxide Inorganic acid salts such as chlorates, sulfates, phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate; benzene sulfonate, p-toluene sulfonate, etc.
- an acid for example, hydrohalides such as hydrofluorate, hydrochloride, hydrobromide, hydroiodide; nitrate, peroxide Inorganic acid salts such as chlorates, sulfates, phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane
- Aryl sulfonates organic acids such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, succinate, maleate; and ornithate, glutamate, aspartate, etc.
- an additional base other than the above base is preferably used.
- Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or an aqueous solution thereof, or 1, 8-diazabicyclo [5.4.0] undec-7-ene can be mentioned, and an aqueous sodium hydroxide solution or 1,8-diazabicyclo [5.4.0] undec-7-ene is preferable.
- the amount of the base is usually 1 to 10 equivalents, preferably 1 to 1.1 equivalents, relative to the compound represented by the formula (II).
- the reaction temperature in this step is usually -80 ° C to 40 ° C, preferably -40 ° C to 20 ° C.
- the reaction time in this step is usually 1 hour to 72 hours, preferably 2 hours to 30 hours.
- Step 3 is a solution containing a compound represented by formula (X) (corresponding to a compound represented by formula (III) in which R 1 is an isopropyl group and R 2 is a methyl group).
- a compound represented by formula (X) corresponding to a compound represented by formula (III) in which R 1 is an isopropyl group and R 2 is a methyl group.
- Crystals of the compound represented by the formula (VII) are 5.2 °, 10.5 °, 15.8 °, 26.5 °, and 26 in powder X-ray diffraction obtained by irradiation with copper K ⁇ rays. It has a main peak at a diffraction angle (2 ⁇ ) of .6 °.
- the above diffraction angle value includes a numerical value within a range of ⁇ 0.2 °. Need to be understood. Therefore, not only crystals that completely match the diffraction angle described above, but also 5.2 ⁇ 0.2 °, 10.5 ⁇ 0.2 °, 15.8 ⁇ 0.2 °, 26.5 ⁇ 0.2.
- a crystal having a main peak at a diffraction angle (2 ⁇ ) of 2 ° and 26.6 ⁇ 0.2 ° is the same and is included in the present invention.
- ⁇ 0.2 ° indicates a numerical value in a range of + 0.2 ° to ⁇ 0.2 ° with respect to a specific numerical value.
- “5.2 ⁇ 0.2 °” indicates a numerical value in the range of 5.0 ° to 5.4 °.
- the solution used in this step is not particularly limited as long as it does not inhibit crystallization of the compound represented by the formula (VII), but an ethyl acetate solution is preferable.
- Crystallization of the crystal of the compound represented by the formula (VII) can be preferably performed under the condition of ⁇ 20 ° C. to 30 ° C., more preferably under the condition of ⁇ 5 ° C. to 5 ° C. Can do.
- the compound represented by the formula (X) is separated into the compound represented by the formula (VII) and the compound represented by the formula (IX) by using optically active column chromatography. It can also be done.
- the manufacturing method of this invention can also be performed according to the following.
- Step 4 This step is a step of optically resolving the compound represented by the formula (XI) to obtain a compound represented by the formula (VI) and a compound represented by the formula (VIII).
- Optical resolution can be performed using optically active column chromatography.
- the compound represented by Formula (VI) can be obtained by performing optical resolution using an enzyme.
- Optical resolution using an enzyme can be performed by reacting a compound represented by the formula (XI) with an enzyme that selectively hydrolyzes the compound represented by the formula (VIII) in an inert solvent.
- the inert solvent used in this step is not particularly limited as long as it does not inhibit the reaction, but is preferably a mixed solvent of a buffer solution and an organic solvent.
- the buffer solution include an acetate buffer solution, a phosphate buffer solution, a citrate buffer solution, a borate buffer solution, a tartrate buffer solution, or a Tris buffer solution, and preferably a phosphate buffer solution, More preferred is a phosphate buffer.
- organic solvents examples include nitrile solvents such as acetonitrile; ether solvents such as diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; saturated hydrocarbon solvents such as hexane and pentane; aromatic hydrocarbon solvents such as benzene, toluene, and chlorobenzene; Ketone solvents such as acetone and 2-butanone; amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; alcohol solvents such as methanol and ethanol; or dimethyl sulfoxide Examples thereof include sulfoxide solvents, and dimethyl sulfoxide is preferred.
- nitrile solvents such as acetonitrile
- ether solvents such as diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran
- saturated hydrocarbon solvents such as hexane
- the enzyme used in this step is not particularly limited as long as it is an enzyme that selectively hydrolyzes the compound represented by formula (VIII), but preferably a lipase derived from Candida antarctica (for example, CHIRAZYME L-2, C3, CHIRAZYME L-2, C4, CHIRAZYME L-2, CA, CHIRAZYME L-2, CB), a lipase derived from Candida rugosa (eg, lipase AY “Amano” 30), or a lipase from Thermomyces lanuginosus, such as lipase A from Z.
- a lipase derived from Candida antarctica for example, CHIRAZYME L-2, C3, CHIRAZYME L-2, C4, CHIRAZYME L-2, CA, CHIRAZYME L-2, CB
- a lipase derived from Candida rugosa eg, lipase AY “Amano” 30
- the amount of the enzyme used in this step is usually 1/100 to 10 times the mass of the mixture of the compound (1) and the compound (2), preferably 1/50 to 1 times the mass. More preferably, the mass is 1/20 to 1/5 times the mass.
- the reaction temperature in this step is usually 0 ° C. to 80 ° C., preferably 10 ° C. to 65 ° C., more preferably 10 ° C. to 30 ° C.
- the reaction time in this step is usually 1 hour to 120 hours, preferably 5 hours to 80 hours, and more preferably 10 hours to 60 hours.
- Step 5 In this step, the compound represented by formula (VII) or a pharmacologically acceptable salt thereof is obtained by bringing the compound represented by formula (VI) into contact with the compound represented by formula (II) or a salt thereof. Is a process of manufacturing. This step can be performed in the same manner as in step 2.
- Step 6 the compound represented by formula (IX) or a pharmacologically acceptable salt thereof is obtained by bringing the compound represented by formula (VIII) into contact with the compound represented by formula (II) or a salt thereof. Is a process of manufacturing. This step can be performed in the same manner as in step 2.
- Examples of pharmacologically acceptable salts of the compounds represented by formula (III), formula (VII), and formula (IX) include acid addition salts with acids such as hydrofluoride, hydrochloride, bromide, and the like.
- Hydrohalates such as hydrogenates and hydroiodides
- inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates
- acetic acid malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate
- organic acid salts such as acid salts
- amino acid salts such as ornithate, glutamate, and aspartate.
- base addition salts with bases include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; dibenzylamine salts , Morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl -N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, organic amine salt such as tris (hydroxymethyl) aminomethane salt; amino acid salt such as arginine salt;
- the compound represented by the formula (III) or a pharmacologically acceptable salt thereof may exist as a solvate, and these solvates are also represented by the compound represented by the formula (III) or a pharmacologically thereof. Included in acceptable salts.
- the solvate is not particularly limited as long as it is pharmacologically acceptable, but specifically, a hydrate, an ethanol solvate and the like are preferable, and a hydrate is more preferable.
- the products of the above steps 1 to 6 may be subjected to conventional methods, for example, (1) a method of concentrating the reaction solution as it is, (2) removing insoluble matters by filtration, and removing the filtrate. Method of concentration, (3) Method of adding water and solvent immiscible with water (for example, dichloromethane, diethyl ether, ethyl acetate, toluene, etc.) to extract the product, (4) Crystallized or precipitated
- the product can be isolated from the reaction mixture by a method such as filtration.
- the isolated product can be purified by a conventional method, for example, vacuum distillation, atmospheric distillation, recrystallization, reprecipitation, various chromatographies and the like, if necessary.
- the product of each step can be used in the next step without isolation or purification.
- the compounds represented by formula (III), formula (VII), and formula (IX) obtained by the method of the present invention are useful as prodrugs for TAFIa inhibitors. Accordingly, the compounds represented by formula (III), formula (VII), and formula (IX) are used for myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral artery It can be used as a therapeutic agent for embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis.
- the compound represented by formula (I) (that is, fluorous alkyl carbonate derivative) is a 1- (acyloxy) alkyl carbamate other than the compounds represented by formula (III), formula (VII), and formula (IX). It can also be used for the purpose of producing derivatives.
- 1 H-NMR means “nuclear magnetic resonance spectrum”
- CDCl 3 in parentheses means deuterated chloroform as a measurement solvent.
- TMS tetramethylsilane
- methyl tert-butyl ether (70 mL) and water (70 mL) were added, and the mixture was stirred and separated.
- the organic layer was washed with water (70 mL), 10% brine (70 mL), 3% sodium bicarbonate 10% brine (70 mL). Further, the organic layer was washed 3 times with 3% sodium hydrogen carbonate 10% brine (70 mL) to remove nitrophenol.
- the organic layer was washed with 20% brine (70 mL) and then concentrated under reduced pressure to about 10 mL.
- the obtained filtrate was concentrated under reduced pressure to 5 L, ethyl acetate (7.5 L) was added, and the mixture was concentrated under reduced pressure to 5 L.
- Ethyl acetate (7.5 L) was added to the residue, and the mixture was concentrated again to 5 L under reduced pressure, cooled to 0 ° C., and stirred for 1 hour.
- the precipitated crystals were filtered, and the crystals were washed with cold ethyl acetate (1 L) and dried under reduced pressure to obtain the title compound as white crystals (467 g, yield 93.3% from crude crystals).
- the absolute configuration of the title compound was confirmed by X-ray crystallography.
- Powder X-ray diffraction The title compound crystals were subjected to powder X-ray diffraction obtained by irradiation with copper K ⁇ rays. The results are shown in Table 1 and FIG. Major peaks were observed at diffraction angles (2 ⁇ ) of 5.2 °, 10.5 °, 15.8 °, 26.5 °, and 26.6 °.
- the activated carbon was washed with a methyl tert-butyl ether / hexane solution (1: 1, 60 mL), water (150 mL) was added, the aqueous layer was adjusted to pH 9.6 with triethylamine, and the mixture was separated. The obtained organic layer was washed 5 times with water (300 mL), and the obtained solution was concentrated under reduced pressure to 30 mL to obtain the title compound as a mixed solution with hexane (HPLC quantitative 11.90 g, HPLC quantitative yield). 39.7%, enantiomeric excess 98.4% ee).
- methyl tert-butyl ether (60 mL) and hexane (150 mL) were added, and after separation, the enzyme was removed by filtration.
- the enzyme was washed with a methyl tert-butyl ether / hexane solution (1: 1, 60 mL), and the obtained filtrate was washed with 20% brine (300 mL), and the resulting solution was concentrated under reduced pressure to 30 mL.
- the resulting residue was purified by distillation (pressure fraction: 1.5 kPa, fraction collected at 65-55 ° C.) to give the title compound as a colorless oil (9.28 g, yield: 30.9%, enantiomeric excess 99.4% ee).
- Example 5 [Analysis conditions] In Example 5, the optical purity of 1- ⁇ [(1,1,1,3,3,3-hexafluoro-2-propyloxy) carbonyl] oxy ⁇ ethyl isobutyrate was confirmed by HPLC under the following analytical conditions. .
- the obtained organic layer was mixed and then washed 4 times with 20% brine (10 mL). Water (30 mL) was added to the obtained organic layer, and after stirring, the aqueous layer was adjusted to pH 6.3 with concentrated hydrochloric acid and separated. The obtained organic layer was concentrated under reduced pressure to 20 mL, ethyl acetate (100 mL) was added, and the mixture was concentrated under reduced pressure to 20 mL. Ethyl acetate (100 mL) was added to the residue, concentrated under reduced pressure to 20 mL, heptane (60 mL) was added dropwise, and the mixture was concentrated to dryness to obtain the title compound as an oily compound (crude yield 12.30 g, content 71.0%). HPLC yield 90.0%).
- a 1- (acyloxy) alkyl carbamate derivative can be produced using a fluorous alkyl carbonate derivative.
- the by-product fluorous alcohol can be easily removed by a simple concentration operation, and it was shown that a good-quality 1- (acyloxy) alkyl carbamate derivative can be produced efficiently and simply.
- the production method of the present invention and the fluorous alkyl carbonate derivative used in the method are useful for the production of a 1- (acyloxy) alkylcarbamate derivative.
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Abstract
Description
1-(アシルオキシ)アルコキシカルボニル基は、アミノ基等を有する種々の医薬分子のプロドラッグ化に利用されている。アミノ基を有する医薬分子は当該基を導入しプロドラッグ化されることにより、1-(アシルオキシ)アルキルカルバメート誘導体となる(非特許文献1、2)。
特許文献1には、TAFIa阻害活性を示す化合物(特許文献1の実施例15、及び40)のプロドラッグとして、1-(アシルオキシ)アルキルカルバメート誘導体(特許文献1の実施例20、22、23、27,28、29、30、31、及び32)が示されている。
1-(アシルオキシ)アルキルカルバメート誘導体の合成法としては、特許文献2~8等に示される方法が知られている。しかし、これらの方法は、多段階の反応工程を必要とすること、収率が低いこと、及び除去が困難な副生成物を生じること等の欠点を有する。
即ち、本発明は、以下の発明を包含する。
式(I)
(2)
フルオラスアルキル基が1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である、(1)に記載された製造方法。
(3)
R1がイソプロピル基であり、R2がメチル基である、(1)又は(2)に記載された製造方法。
(4)
式(VI)
(5)
式(VIII)
(6)
式(I)
(7)
フルオラスアルキル基が1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である、(6)に記載された化合物。
(8)
R1がイソプロピル基であり、R2がメチル基である、(6)又は(7)に記載された化合物。
(9)
式(VI)
(10)
式(VIII)
(11)
式(IV)
(12)
フルオラスアルキル基が1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である、(11)に記載された製造方法。
(13)
R1がイソプロピル基であり、R2がメチル基である、(11)又は(12)に記載された製造方法。
(14)
式(XI)
(15)
酵素がCandida antarctica由来のリパーゼ、Candida rugosa由来のリパーゼ、又はThemomyces lanuginosus由来のリパーゼである、(14)に記載された製造方法。
(16)
酵素がCandida antarctica由来のリパーゼである、(15)に記載された製造方法。
(17)
酵素がCHIRAZYME L-2,C4である、(16)に記載された製造方法。
(18)
不活性溶媒が緩衝液を含む溶媒である、(14)~(17)のいずれか1項に記載された製造方法。
(19)
不活性溶媒がリン酸緩衝液を含む溶媒である、(14)~(17)のいずれか1項に記載された製造方法。
(20)
銅のKα線の照射で得られる粉末X線回折において、5.2±0.2°、10.5±0.2°、15.8±0.2°、26.5±0.2°、及び26.6±0.2°の回折角度(2θ)に主要なピークを示すことを特徴とする、式(VII)
(21)
式(X)
式(VII)
(22)
溶液が酢酸エチルを含む溶液である、(21)に記載された製造方法。
(23)
晶析が-5℃~5℃の条件下で行われる、(21)又は(22)に記載された製造方法。
(24)
(3)に記載の製造方法に次いで行われる、(21)~(23)のいずれか1項に記載された製造方法。
R1における「C1~C4アルキル基」は、好適には、メチル基、エチル基、イソプロピル基、又はtert-ブチル基であり、更に好適には、イソプロピル基、又はtert-ブチル基であり、最も好適には、イソプロピル基である。
R1における「C3~C6シクロアルキル基」は、好適には、シクロブチル基、シクロペンチル基、又はシクロヘキシル基であり、更に好適には、シクロペンチル基、又はシクロヘキシル基であり、最も好適には、シクロヘキシル基である。
R1全体としては、好適には、メチル基、エチル基、イソプロピル基、tert-ブチル基、又はシクロヘキシル基であり、更に好適には、イソプロピル基、tert-ブチル基、又はシクロヘキシル基であり、最も好適には、イソプロピル基である。
R2における「C1~C4アルキル基」は、好適には、メチル基、エチル基、又はイソプロピル基であり、更に好適には、メチル基、又はエチル基であり、最も好適には、メチル基である。
Aにおける「フルオラスアルキル基」は、好適には、2,2,2-トリフルオロエチル基、2,2,3,3,3-ペンタフルオロ-1-プロピル基、1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基、2,2,3,4,4,4-ヘキサフルオロ-1-ブチル基、2,2,3,3,4,4,4-ヘプタフルオロ-1-ブチル基、又はノナフルオロ-tert-ブチル基であり、更に好適には、2,2,2-トリフルオロエチル基、2,2,3,3,3-ペンタフルオロ-1-プロピル基、1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基、2,2,3,4,4,4-ヘキサフルオロ-1-ブチル基、又は2,2,3,3,4,4,4-ヘプタフルオロ-1-ブチル基であり、最も好適には、1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である。
本工程は、式(IV)[ここで、R1はC1~C4アルキル基又はC3~C6シクロアルキル基を示し、R2はC1~C4アルキル基又は水素原子を示す。]で表される化合物と、式(V)[ここで、Aはフルオラスアルキル基を示す。(ここで、フルオラスアルキル基は40%以上の水素原子がフッ素原子に置換されたC2~C11アルキル基を示す。)]で表される化合物を接触せしめることにより、式(I)[ここで、R1、R2及びAは上記で定義した通りである。]で表される化合物(即ち、フルオラスアルキルカーボネート誘導体)を製造する工程である。
本工程は、式(I)[ここで、R1はC1~C4アルキル基又はC3~C6シクロアルキル基を示し、R2はC1~C4アルキル基又は水素原子を示し、Aはフルオラスアルキル基を示す。(ここで、フルオラスアルキル基は40%以上の水素原子がフッ素原子に置換されたC2~C11アルキル基を示す。)]で表される化合物(即ち、フルオラスアルキルカーボネート誘導体)と式(II)で表される化合物又はその塩とを接触せしめることにより、式(III)[ここで、R1及びR2は上記で定義した通りである。]で表される化合物(即ち、1-(アシルオキシ)アルキルカルバメート誘導体)又はその薬理上許容される塩を製造する工程である。
本工程により、式(I)で表される化合物のAに対応するフルオラスアルコールが副生する。かかる化合物として、例えば、2,2-ジフルオロエタノール、2,2,2-トリフルオロエタノール、2,2,3,3,3-ペンタフルオロ-1-プロパノール、1,1,1,3,3,3-ヘキサフルオロ-2-プロパノール、2,2,3,4,4,4-ヘキサフルオロ-1-ブタノール、2,2,3,3,4,4,4-ヘプタフルオロ-1-ブタノール、ノナフルオロ-tert-ブタノール、2,2,3,3,4,4,5,5-オクタフルオロ-1-ペンタノール、1H,1H-ノナフルオロ-1-ペンタノール、1H,1H,2H,2H-ノナフルオロ-1-ヘキサノール、1H,1H,7H-ドデカフルオロ-1-ヘプタノール、1H,1H-トリデカフルオロ-1-ヘプタノール、1H,1H,2H,2H-トリデカフルオロ-1-n-オクタノール、1H,1H-ペンタデカフルオロ-1-オクタノール、1H,1H,9H-ヘキサデカフルオロ-1-ノナノール、1H,1H-ヘプタデカフルオロ-1-ノナノール、1H,1H,2H,2H-ヘプタデカフルオロ-1-デカノール、1H,1H-ノナデカフルオロ-1-デカノール、1H,1H,11H-エイコサフルオロ-1-ウンデカノールを挙げることができるが、特に、C2~C6のアルキル基を有するフルオラスアルコールは低沸点の化合物であるため、単純な濃縮操作により、容易に除去することができる。
式(II)で表される化合物が酸との酸付加塩(例えば、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等のハロゲン化水素酸塩;硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩;メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩等の低級アルカンスルホン酸塩;ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のアリールスルホン酸塩;酢酸、りんご酸、フマル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩;及びオルニチン酸塩、グルタミン酸塩、アスパラギン酸塩等のアミノ酸塩を挙げることができ、好適には、p-トルエンスルホン酸塩)である場合は、好適には上記塩基以外の追加の塩基を用いる。該塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、若しくは炭酸水素カリウム、若しくはこれらの水溶液、又は1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンを挙げることができ、好適には、水酸化ナトリウム水溶液、又は1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンである。該塩基の量は、式(II)で表される化合物に対して、通常、1~10当量であり、好適には、1~1.1当量である。
本工程は、式(X)で表される化合物(式(III)で表される化合物のうち、R1がイソプロピル基であり、R2がメチル基である化合物に相当する。)を含む溶液から式(VII)で表される化合物の結晶を晶析することにより、式(VII)で表される化合物又はその薬理上許容される塩を製造する工程である。 式(VII)で表される化合物の結晶は、銅のKα線の照射で得られる粉末X線回折において、5.2°、10.5°、15.8°、26.5°、及び26.6°の回折角度(2θ)に主要なピークを示すことを特徴とする。一般に、粉末X線回折における回折角度(2θ)は、±0.2°の範囲内で誤差が生じ得るため、上記の回折角度の値は±0.2°の範囲内の数値も含むものとして理解される必要がある。従って、上記の回折角度と完全に一致する結晶だけでなく、5.2±0.2°、10.5±0.2°、15.8±0.2°、26.5±0.2°、及び26.6±0.2°の回折角度(2θ)に主要なピークを有する結晶も同一であり、本発明に含まれる。本発明において「±0.2°」とは、特定の数値に対し+0.2°~-0.2°の範囲の数値であることを示す。例えば、「5.2±0.2°」とは、5.0°~5.4°の範囲の数値であることを示す。
本工程は、式(XI)で表される化合物を光学分割し、式(VI)で表される化合物及び式(VIII)で表される化合物を得る工程である。光学分割は光学活性カラムクロマトグラフィーを用いて行うことができる。
本工程に用いられる酵素は、式(VIII)で表される化合物を選択的に加水分解する酵素であれば特に制限はないが、好適にはCandida antarctica由来のリパーゼ(例えば、CHIRAZYME L-2,C3、CHIRAZYME L-2,C4、CHIRAZYME L-2,CA、CHIRAZYME L-2,CB)、Candida rugosa由来のリパーゼ(例えば、リパーゼAY「アマノ」30)、又はThemomyces lanuginosus由来のリパーゼ(例えば、CHIRAZYME L-8.1)であり、より好適にはCandida antarctica由来のリパーゼであり、更により好適にはCHIRAZYME L-2,C4である。本工程に用いられる酵素の量は、化合物(1)と化合物(2)の混合物の質量に対して、通常1/100~10倍の質量であり、好適には1/50~1倍の質量であり、より好適には1/20~1/5倍の質量である。
本工程の反応時間は、通常1時間~120時間であり、好適には5時間~80時間であり、より好適には10時間~60時間である。
本工程は、式(VI)で表される化合物と式(II)で表される化合物又はその塩とを接触せしめることにより、式(VII)で表される化合物又はその薬理上許容される塩を製造する工程である。本工程は工程2と同様な方法で行うことができる。
本工程は、式(VIII)で表される化合物と式(II)で表される化合物又はその塩とを接触せしめることにより、式(IX)で表される化合物又はその薬理上許容される塩を製造する工程である。本工程は工程2と同様な方法で行うことができる。
なお、式(I)で表される化合物(即ち、フルオラスアルキルカーボネート誘導体)は、式(III)、式(VII)、及び式(IX)で表される化合物以外の1-(アシルオキシ)アルキルカルバメート誘導体を製造する目的でも使用することができる。
イソ酪酸1-{[(4-ニトロフェノキシ)カルボニル]オキシ}エチル(Bioorg.Med.Chem.Lett.,7,p.1811-1816(1997))(7.0g,23.54mmol)及び1,1,1,3,3,3-ヘキサフルオロ-2-プロパノール(11.87g,70.65mmol)のアセトニトリル(35mL)溶液を0~5℃に冷却後、トリエチルアミン(3.42mL,24.72mmol)を滴下し、同温で4時間攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(70mL)および水(70mL)を加え、攪拌後、分液した。有機層を水(70mL)、10%食塩水(70mL)、3%炭酸水素ナトリウム10%食塩水(70mL)で洗浄した。更に有機層を3%炭酸水素ナトリウム10%食塩水(70mL)で3回洗浄し、ニトロフェノールを除去した。有機層を20%食塩水(70mL)で洗浄後、約10mLまで減圧濃縮した。得られた残渣を蒸留精製(減圧度1kPa,75~80℃留分を分取)し、標題化合物を油状物質として得た(6.02g,収率78.1%)。
1H-NMR(CDCl3) δ:6.82(1H,q,J=5.5Hz),5.55(1H,hept,J=5.5Hz),2.58(1H,hept,J=7.0Hz),1.58(3H,d,J=5.5 Hz),1.18(6H,d,J=7.0Hz).
イソ酪酸1-{[(4-ニトロフェノキシ)カルボニル]オキシ}エチル(230g,774mmol)及び1,1,1,3,3,3-ヘキサフルオロ-2-プロパノール(260g,1547mmol)のアセトニトリル(1150mL)溶液を0~5℃に冷却後、トリエチルアミン(82.23g,812mmol)を滴下し、同温で4時間攪拌した。反応の完結を確認後、0-5℃のメチルtert-ブチルエーテル(1150mL)およびn-ヘキサン(1150mL)を加え、冷水(2300mL)を加え、攪拌後、分液した。有機層を冷水(2300mL)で4回洗浄後、約345mLまで減圧濃縮した。得られた残渣を蒸留精製(減圧度1.5kPa,70~82℃留分を分取)し、標題化合物を油状物質として得た(222.51g,収率88.2%)。
1H-NMR(CDCl3) δ:7.60(1H,d,J=1.0Hz),6.78(1H,q,J=5.5Hz),6.74(1H,s),5.03(1H,brs),3.87-3.79(1H,m),3.22-3.10(2H,m),2.88(1H,dd,J=15.0,8.5Hz),2.78(1H,dt,J=15.0,3.5Hz),2.70-2.64(1H,m),2.53(1H,tt,J=7.0,7.0Hz),2.14-2.07(2H,m),1.90-1.84(2H,m),1.78-1.57(5H,m),1.49-1.41(2H,m),1.44(1H,t,J=5.5Hz),1.15(6H,d,J=7.0Hz),1.15-1.05(2H,m),0.96(3H,d,J=6.5Hz).
理論値:C,61.18;H,8.26;N,9.31;O,21.26
実測値:C,60.92;H,8.16;N,9.35;O,21.29
標題化合物の結晶について、銅のKα線の照射で得られる粉末X線回折を行った。結果を表1及び図1に示す。5.2°、10.5°、15.8°、26.5°、及び26.6°の回折角度(2θ)に主要なピークが認められた。
(R)-イソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロポキシ)カルボニル]オキシ}エチル:[α]D 25=+8.56(c=1.0,CHCl3)
(S)-イソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロポキシ)カルボニル]オキシ}エチル:[α]D 25=-8.43(c=1.0,CHCl3)
(R)-イソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロポキシ)カルボニル]オキシ}エチル:2980,1786,1756,1386,1366,1300,1258,1233,1200,1111,1052,1005,936,899,863,780,758,709,689,518,and 479cm-1.
(S)-イソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロポキシ)カルボニル]オキシ}エチル:2980,1786,1757,1386,1365,1301,1258,1232,1200,1111,1053,1005,936,899,863,780,758,710,689,518,and 480cm-1.
りん酸二水素カリウム(13.5g,99.20mmol)と、りん酸水素カリウム(36.0g,206.67mmol)の水(300mL)溶液を、20°Cに冷却後、CHIRAZYME L-2,C4(3.0g)を加え、メチルtert-ブチルエーテル(90mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(30.00g,91.97mmol)を加えた後、同温で38時間攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(60mL)、ヘキサン(150mL)を加え、酵素をろ去した。メチルtert-ブチルエーテル/ヘキサン溶液(1:1,60mL)で、酵素を洗浄後、得られた混合液を分液した。得られた有機層に活性炭(3.0g)を加え、20°Cで30分攪拌後、活性炭をろ去した。活性炭をメチルtert-ブチルエーテル/ヘキサン溶液(1:1,60mL)で洗浄後、水(150mL)を加え、トリエチルアミンを用いて水層をpH9.6に調整した後、混合液を分液した。得られた有機層を、水(300mL)で5回洗浄後、得られた溶液を30mLまで減圧濃縮し、標題化合物をヘキサンとの混合液として得た(HPLC定量11.90g,HPLC定量収率39.7%,エナンチオマー過剰率98.4%ee)。
りん酸二水素カリウム(14.4g,105.81mmol)と、りん酸水素カリウム(33.9g,194.62mmol)の水(300mL)溶液を、20°Cに冷却後、CHIRAZYME L-2,C4(3.0g)を加え、メチルtert-ブチルエーテル(90mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(30.00g,91.97mmol)を加えた後、同温で21時間攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(60mL)、ヘキサン(150mL)を加え、分液後、酵素をろ去した。メチルtert-ブチルエーテル/ヘキサン溶液(1:1,60mL)で、酵素を洗浄後、得られたろ液を、20%食塩水(300mL)で洗浄後、得られた溶液を30mLまで減圧濃縮した。得られた残渣を蒸留精製(減圧度1.5kPa,65-55℃留分を分取)し、標題化合物を無色油状物質として得た(9.28g,収率30.9%,エナンチオマー過剰率99.4%ee)。
1H-NMR(500MHz,CDCl3):δ 6.82(1H,q,J=5.5Hz),5.55(1H,hept,J=5.5Hz),2.58(1H,hept,J=7.0Hz),1.59(3H,d,J=5.5Hz),1.18(6H,d,J=7.0Hz).
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、CHIRAZYME L-2, C4.1(5.0mg)を加え、メチルtert-ブチルエーテル(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率38.4%,エナンチオマー過剰率99.4%ee)。
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、CHIRAZYME L-2, C3(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率33.4%,エナンチオマー過剰率99.4%ee)。
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、CHIRAZYME L-2, CB(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率16.2%,エナンチオマー過剰率64.4%ee)。
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、CHIRAZYME L-5, CA(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率12.0%,エナンチオマー過剰率66.4%ee)。
りん酸緩衝液(0.5 M,pH7.0,2.5mL)に、CHIRAZYME L-8.1(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率45.3%,エナンチオマー過剰率30.0%ee)。
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、リパーゼAY「アマノ」30(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率41.3%,エナンチオマー過剰率31.6%ee)。
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、リパーゼAYS「アマノ」(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率41.6%,エナンチオマー過剰率37.4%ee)。
りん酸緩衝液(0.5M,pH7.0,2.5mL)に、Novozyme 435(5.0mg)を加え、ヘキサン(0.5mL)を加え、ラセミ体のイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル(50mg,0.153mmol)を加えた後、室温で終夜攪拌した。反応の完結を確認後、メチルtert-ブチルエーテル(2.0mL)を加え、酵素をろ去した。得られた混合液を分液し、減圧濃縮後、標題化合物を濃縮乾固品として得た(HPLC定量収率41.1%,エナンチオマー過剰率84.8%ee)。
実施例5は、下記の分析条件下、HPLCによりイソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチルの光学純度を確認した。
移動相:(A)0.1%TFAaq.、(B)Acetonitrile=52/48
カラム温度 :38℃
流量 :1mL/min
検出 :UV 215nm
分析時間 :8min
希釈液 :MeCN
注入量 :10μL injection
保持時間 :
(R)-イソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル:5.1min
(S)-イソ酪酸1-{[(1,1,1,3,3,3-ヘキサフルオロ-2-プロピロキシ)カルボニル]オキシ}エチル:5.8min
1H-NMR(CDCl3) δ:7.58(1H,d,J=1.5Hz),6.78(1H,q,J=5.5Hz),6.74(1H,s),4.98(1H,t,J=5.5Hz),3.84(1H,tt,J=12.0,4.0Hz),3.22-3.11(2H,m),2.86(1H,dd,J=15.0,8.5Hz),2.78(1H,dt,J=15.0,3.0Hz),2.70-2.64(1H,m),2.52(1H,tt,J=7.0,7.0Hz),2.14-2.07(2H,m),1.90-1.84(2H,m),1.78-1.57(5H,m),1.49-1.41(2H,m),1.44(1H,d,J=7.0Hz),1.15(6H,dd,J=6.5,0.5Hz),1.15-1.05(2H,m),0.95(3H,d,J=6.5Hz).
実施例6、7は下記の分析条件下、HPLCにより、生成物のジアステレオマー比を確認した。
移動相:n-ヘキサン/エタノール/ジエチルアミン/酢酸=65/35/0.1/0.1(v/v)
カラム温度 :40℃
流量 :1mL/min
検出 :UV 220nm
分析時間 :15min
希釈液 :エタノール
注入量 :20μL
保持時間 :
(2S)-5-({[(1R)-1-(イソブチリルオキシ)エトキシ]カルボニル}アミノ)2-{[1-(trans-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}吉草酸:6.1min
(2S)-5-({[(1S)-1-(イソブチリルオキシ)エトキシ]カルボニル}アミノ)2-{[1-(trans-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}吉草酸:12.3min
Claims (24)
- フルオラスアルキル基が1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である、請求項1に記載された製造方法。
- R1がイソプロピル基であり、R2がメチル基である、請求項1又は2に記載された製造方法。
- フルオラスアルキル基が1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である、請求項6に記載された化合物。
- R1がイソプロピル基であり、R2がメチル基である、請求項6又は7に記載された化合物。
- フルオラスアルキル基が1,1,1,3,3,3-ヘキサフルオロ-2-プロピル基である、請求項11に記載された製造方法。
- R1がイソプロピル基であり、R2がメチル基である、請求項11又は12に記載された製造方法。
- 酵素がCandida antarctica由来のリパーゼ、Candida rugosa由来のリパーゼ、又はThemomyces lanuginosus由来のリパーゼである、請求項14に記載された製造方法。
- 酵素がCandida antarctica由来のリパーゼである、請求項15に記載された製造方法。
- 酵素がCHIRAZYME L-2,C4である、請求項16に記載された製造方法。
- 不活性溶媒が緩衝液を含む溶媒である、請求項14~17のいずれか1項に記載された製造方法。
- 不活性溶媒がリン酸緩衝液を含む溶媒である、請求項14~17のいずれか1項に記載された製造方法。
- 溶液が酢酸エチルを含む溶液である、請求項21に記載された製造方法。
- 晶析が-5℃~5℃の条件下で行われる、請求項21又は22に記載された製造方法。
- 請求項3に記載の製造方法に次いで行われる、請求項21~23のいずれか1項に記載された製造方法。
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US15/739,361 US10308612B2 (en) | 2015-06-26 | 2016-06-24 | Method for producing 1-(acyloxy)alkyl carbamate derivative |
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US4916230A (en) | 1984-07-02 | 1990-04-10 | Merck & Co., Inc. | Process for preparing novel N-(acyloxy-alkoxy)carbonyl derivatives useful as bioreversible prodrug moieties for primary and secondary amine functions in drugs |
US6818787B2 (en) | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
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US7662987B2 (en) | 2003-07-15 | 2010-02-16 | Xenoport, Inc. | Methods for synthesis of acyloxyalkyl compounds |
EP2371815A1 (en) | 2003-12-30 | 2011-10-05 | XenoPort, Inc. | Sythesis of acyloxyalkyl carbamate prodrugs and intermediates thereof |
WO2010017504A1 (en) | 2008-08-07 | 2010-02-11 | Xenoport, Inc. | Methods of synthesizing 1-(acyloxy)-alkyl carbamate prodrugs |
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US20140243544A1 (en) * | 2013-02-26 | 2014-08-28 | Xenoport, Inc. | Method of making 1-(acyloxy)-alkyl carbamate compounds |
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Title |
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KAZUHIDE ASHIZAWA: "Shio Kesshokei no Saitekika to Kesshoka Gijutsu", PHARM TECH JAPAN, vol. 18, no. 10, 2002, pages A1 - 96, XP008177312 * |
LUO, Z. ET AL.: "Fluorous Boc (FBoc) Carbamates: New Amine Protecting Groups for Use in Fluorous Synthesis", JOURNAL OF ORGANIC CHEMISTRY, vol. 66, no. 12, 2001, pages 4261 - 4266, XP001061425 * |
NORIAKI HIRAYAMA: "Yuki Kagobutsu Kessho Sakusei Handbook", 25 July 2008 (2008-07-25), pages 57 - 84, XP008183996 * |
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